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Novel developments for applications of alphavirusvectors in gene therapy

机译:α病毒载体在基因治疗中的应用新进展

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As a prerequisite for gene therapy applications, alphavirus-mediated delivery of reporter genes to different brain regions in rodents has resulted in local, high-level expression of a transient nature. Infection of human prostate tumor cell lines with recombinant Semliki Forest virus (SFV)-LacZ particles demonstrated a strong induction of apoptosis that led to premature cell death. Injection of self-replicative SFV-LacZ RNA showed in prophylactic and therapeutic effects in animals. Furthermore, injection of SFV vectors expressing interleukin-12 resulted in tumor regression in a mouse B16 melanoma tumor model. Similarly, injection of SFV vectors expressing GFP, β- galactosidase or even empty SFV vectors led to p53-independent induction of apoptosis in nude mice with implanted human lung carcinomas. Repeated injections showed improved anti-tumor responses without any visible immune reaction against injected SFV particles. The envelope structure of alphaviruses has been modified to allow cell/tissue specific targeting. Moreover, SFV vectors have been used for the production of retrovirus-like particles. Extensive development on alphavirus vectors has resulted in novel non-cytopathogenic and replication-persistent forms. Overall, alphavirus vectors can be considered highly attractive for future gene therapy applications.
机译:作为基因治疗应用的先决条件,α病毒介导的报道基因向啮齿动物中不同大脑区域的传递已经导致了局部高水平的瞬时表达。重组Semliki森林病毒(SFV)-LacZ颗粒感染人前列腺肿瘤细胞系显示出强烈的凋亡诱导作用,导致细胞过早死亡。注射自我复制的SFV-LacZ RNA在动物中具有预防和治疗作用。此外,注射表达白介素12的SFV载体在小鼠B16黑素瘤肿瘤模型中导致肿瘤消退。同样,注射表达GFP,β-半乳糖苷酶的SFV载体,甚至空的SFV载体,都会在植入人肺癌的裸鼠中诱导p53独立的凋亡诱导。重复注射显示出改善的抗肿瘤反应,而对注射的SFV颗粒没有任何可见的免疫反应。甲病毒的包膜结构已被修改,以允许细胞/组织特异性靶向。此外,SFV载体已用于生产逆转录病毒样颗粒。在alphavirus载体上的广泛开发已导致新型的非致细胞病和复制持久形式。总的来说,α病毒载体可被认为对未来的基因治疗应用非常有吸引力。

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